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PURPOSE: Although the conventional gamma ray brachytherapy has been successful in treating endometrioid endometrial adenocarcinoma (EC), the molecular and cellular mechanisms of this anti-tumorigenic response remain unclear. Therefore, we investigated whether gamma ray irradiation induces changes in the number of FoxP3+ T-regulatory lymphocytes (Tregs), CD56+ natural killer cells (NK), and the expression of progesterone receptor membrane component 1 (PGRMC1) in the tumor microenvironment (TME). MATERIALS AND METHODS: According to the inclusion criteria, 127 cases were selected and grouped into irradiation-treated (Rad+) and control (underwent surgery) groups and analyzed using immunohistochemistry. Predictive prognostic values were analyzed using Mann-Whitney U test, ROC analysis, relative risk, log-rank, Spearman rank tests and multivariate Cox's regression. RESULTS: We observed significant differences (p < 0.001) between the radiation-treated patients and the control groups in FoxP3+ Tregs numbers, CD56+ NK cells and PGRMC1 expression. Gamma ray induced a 3.71- and 3.39-fold increase in the infiltration of FoxP3+ cells, CD56+ NK cells, respectively and 0.0034-fold change in PGRMC1 expression. Univariate and multivariate analyses revealed predictive role of the parameters. In the irradiated patients' group, inverted correlations between clinical unfavorable outcome, FoxP3+ Tregs and CD56+ NK cells were observed. CONCLUSION: Our results suggest an immune-modulating role, specifically by increasing immune cell infiltration, of gamma radiation in the TME which may potentially be utilized as biomarkers in prognostic values.
RESUMEN
OBJECTIVE: Recurrent miscarriage (RM) is a multifactorial condition that involves frequent uterine anatomical abnormalities, parental karyotype abnormalities, and clotting disorders. We investigate the potential roles of endometrium FoxP3+ Tregs and CD56+ cells (uNK cells) and endometrial expression of PGRMC1 in the development of recurrent miscarriage. STUDY DESIGN: This prospective study included 102 out of 286 cases of SA patients. The cases were divided into groups with RM (+RM) and without RM (-RM). Immunohistochemistry staining was made using primary antibodies to FoxP3, CD56, and PGRMC1 in both groups. Morphometry analyses were carried out in 10 non-overlapping high power fields. Mann-Whitney U test, Fisher two-tail test, correlation analysis and relative risk (RR) were evaluated. A pâ¯<â¯0.05 was considered statistically significant. RESULTS: An increased presence of CD56-positive (pâ¯<â¯0.001) and FoxP3+ Treg (pâ¯=â¯0.0005) cells was found in the endometrium, with a reduction in PGRMC1 expression compared with -RM group (pâ¯=â¯0.004). A positive correlation was shown between the number of CD56-positive cells and FoxP3+ cells (râ¯=â¯0.55), and an inverse correlation with PGRMC1 (râ¯=⯠-0.35) in theâ¯+â¯RM group. A similar observation was found in the -RM group, with a positive correlation of uNK cell number with the number of pregnancies (pâ¯<â¯0.001; râ¯=â¯0.34). Endometrial infiltration of CD56-positive (pâ¯<â¯0.0001) and FoxP3+ (pâ¯<â¯0.0001) cells revealed an increased relative risk of RM. This increased risk was also revealed in SA with a loss of PGRMC1 expression (pâ¯<â¯0.0001). CONCLUSION: Our prospective study suggests, for the first time, that increased endometrial infiltration of uNK, FoxP3+ Treg cells and a decreased PGRMC1 expression may play potential roles in the development of RM.